Significant survival improvement of patients with recurrent breast cancer in the periods 2001-2008 vs. 1992-2000
© Shigematsu et al; licensee BioMed Central Ltd. 2011
Received: 20 January 2010
Accepted: 31 March 2011
Published: 31 March 2011
It is unclear whether individualized treatments based on biological factors have improved the prognosis of recurrent breast cancer. The purpose of this study is to evaluate the survival improvement of patients with recurrent breast cancer after the introduction of third generation aromatase inhibitors (AIs) and trastuzumab.
A total of 407 patients who received first diagnosis of recurrent breast cancer and treatment at National Kyushu Cancer Center between 1992 and 2008 were retrospectively evaluated. As AIs and trastuzumab were approved for clinical use in Japan in 2001, the patients were divided into two time cohorts depending on whether the cancer recurred before or after 2001. Cohort A: 170 patients who were diagnosed between 1992 and 2000. Cohort B: 237 patients who were diagnosed between 2001 and 2008. Tumor characteristics, treatments, and outcome were compared.
Fourteen percent of cohort A and 76% of cohort B received AIs and/or trastuzumab (P < 0.001). The median overall survival (OS) times after breast cancer recurrence were 1.7 years and 4.2 years for these respective cohorts (P < 0.001). Both the time period and treatment of AIs and/or trastuzumab for recurrent disease were significant prognostic factors in multivariate analysis (cohort B vs. cohort A: HR = 0.70, P = 0.01; AIs and/or trastuzumab for recurrent disease: yes vs. no: HR = 0.46, P < 0.001). When patients were categorized into 4 subgroups by the expression of hormone receptor (HR) and HER-2 status, the median OS times of the HR-positive/HER-2-negative, HR-positive/HER-2-positive, HR-negative/HER-2-positive, and HR-negative/HER-2-negative subtypes were 2.2, 2.4, 1.6, and 1.0 years in cohort A and 4.5, 5.1, 5.0, and 1.4 years in cohort B.
The prognosis of patients with recurrent breast cancer was improved over time following the introduction of AIs and trastuzumab and the survival improvement was apparent in HR- and/or HER-2-positive tumors.
Molecular targeting therapies have recently become available, and tailored treatments based on individual biological factors have already come to play an important role in breast cancer treatment. In the adjuvant setting, a meta-analysis has shown that 5-year adjuvant treatment with tamoxifen (TAM) reduced the annual risk of recurrence and death by more than 30% in patients with estrogen receptor (ER)-positive tumors . In addition, large randomized controlled trials have shown that third-generation aromatase inhibitors (AIs) are more effective than TAM in post-menopausal early breast cancer patients with HR-positive tumors [2–4]. Among women with HER-2-positive early breast cancer, concurrent or sequential use of trastuzumab with, or after, adjuvant chemotherapy significantly improves both disease-free survival and overall survival rates [5–7]. Adjuvant trastuzumab therapy is expected to decrease the breast cancer mortality rate and, as mentioned above, tailored treatments based on individual biological factors have significantly contributed to the prognostic improvement of patients with early stage breast cancer .
Compared with the adjuvant setting, the type of tailored treatments (based on biological factors) that have contributed to the improvement in prognosis for patients with recurrent or advanced breast cancer is less clear. Some retrospective studies have reported that the survival of patients with recurrent breast cancer has improved, over time, with the introduction of new drugs [9–12]. And while it is difficult to ascertain exactly which therapies have contributed to the improved survival of patients with advanced breast cancer , the improvement does seem to be associated with the expression of certain biological factors. Andre et al. (2004) compared the prognosis of metastatic breast cancer patients over two time periods, and showed a significant prolongation of survival over time in patients with HR-positive tumors . This finding suggests that the improvement was related to therapy targeted at patients who had HR-positive tumors. A recent study of an institutional-based review showed that women with HER2/neu-positive disease who received trastuzumab had improved prognosis compared with women with HER2/neu-negative disease . With the introduction of trastuzumab in daily practice, the survival of patients with HER-2-positive disease may be prolonged overtime. Here, we investigate whether the survival of women with recurrent breast cancer has improved following the introduction of new agents, such as AIs and trastuzumab. The use of these drugs for the treatment of recurrent, or metastatic, breast cancer in Japan was approved in 2001. Thus, we compared the prognosis between patients first diagnosed with recurrent breast before 2001 and those first diagnosed after 2001.
Recent studies have shown that intrinsic subtypes are important prognostic and predictive factors in breast cancer. Thus, in both early and advanced stage breast cancer, the intrinsic subtype has been strongly correlated with prognosis [16–18]. In a neoadjuvant setting, chemosensitivity has been shown to differ among breast cancer subtypes [19, 20]. Thus, we also performed an exploratory analysis to determine whether the recent survival improvement in recurrent breast cancer was related to the breast cancer subtype. We classified the patients into four subgroups for this purpose: HR-positive/HER-2-negative; HR-positive/HER-2-positive; HR-negative/HER-2-positive; and HR-negative/HER-2-negative cases. Within each subgroup, we compared the prognosis over time, and evaluated the relationship between the survival improvement and expression of HR and HER-2.
All patient data were collected at the Department of Breast Oncology at the National Kyushu Cancer Center, Fukuoka, Japan. This retrospective analysis was performed in accordance with the ethical regulations of the National Kyushu Cancer Center.
A total of 569 patients who were diagnosed and treated for recurrent breast cancer at the National Kyushu Cancer Center between 1992 and 2008 were eligible for this study. All patients had undergone primary surgery for breast cancer without any evidence of distant metastasis and then were clinically determined to have recurrent breast cancer. The diagnosis of recurrent disease was essentially confirmed by physical examination, X-rays, computer tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy and/or other imaging modalities. A biopsy of metastasis was not essential for the diagnosis of recurrent disease. We excluded 133 (23.3%) cases that lacked either HR or HER-2 expression data, and 29 (5.1%) cases that were not followed-up, or who did not receive treatment after first diagnosis of recurrence. The remaining 407 patients were included in the study. Isolated ipsilateral breast cancer recurrence was excluded from the study because it was difficult to distinguish true recurrence from a new primary lesion. The clinicopathological factors and treatments for primary breast cancer and recurrent disease pertaining to these patients were entered prospectively into the hospital database. Patients were assigned to two cohorts based on the time of their first diagnosis of recurrence. Cohort A included patients diagnosed between 1992 and 2000; Cohort B included patients diagnosed between 2001 and 2008. As outlined above, patients were also assigned to four subgroups according to HR and HER-2 expression. The prognosis of the patients within each group was compared between the two time periods. Survival time was defined as the time from the date of first recurrence to the last follow-up examination, or death. Follow-up was ended in December 2009. The primary aims of this study were to evaluate the association between period of diagnosis of recurrent disease and overall survival (OS). As an exploratory analysis, we also determined the relationship between the survival improvement over time and the breast cancer subtype as defined by HR and HER-2 status.
Because prognostic variables were unevenly divided between the two main cohorts, a multivariate model was created to determine any association between these cohorts and survival rate, after accounting for other prognostic factors. Information regarding the year of first recurrent diagnosis, patient age, primary tumor size, number of positive axillary lymph nodes, HR status, HER-2 status, relapse free interval (RFI), sites of metastases, brain metastasis, adjuvant therapy, and medical treatments for recurrent disease was obtained directly from the database.
ER and/or progesterone receptor assays were performed using either an enzyme immunoassay method (ELISA) or immunohistochemical analysis (IHC). HER-2 status was estimated by either IHC or fluorescence in situ hybridization (FISH) at diagnosis, however most cases were evaluated by IHC. HER-2 FISH were performed for patients in Cohort B. Cases showing overexpression of HER-2/c-erbB2, or HER-2 amplification, were considered to be HER-2-positive. Patients presenting with lung and/or liver and/or brain involvement were classified as having visceral metastases. Patients presenting with other involvements were classified as having non-visceral metastases. There was no limitation on the number or the type of treatments that each patient received.
Associations between the two cohorts and clinicopathological parameters were analyzed using a Chi-square test for categorical variables, and the Wilcoxon rank sum test for continuous variables. Kaplan-Meier survival curves were plotted, and compared using the log-rank test. Cox proportional hazard models were used for both univariate and multivariate analyses. We analyzed new systemic treatment (AI and/or trastuzumab) for recurrent disease as a confounder in the Cox regression model in order to clarify whether introduction of these new agents was the main contributor to the survival improvement over time. The hazard ratios (95% CI) and P values were reported. All tests were two-sided, and P < 0.05 was considered statistically significant. Statistical analyses were carried out using SPSS II software (Version 11 for Windows; SAS Institute, Tokyo).
(n = 170)
(n = 237)
(n = 407)
No. of Patients
No. of Patients
No. of Patients
Median age, years
No. of axillary nodes involved
HR + and HER-2 -
HR + and HER-2 +
HR - and HER-2 +
HR - and HER-2 -
Relapse Free Interval
≤ 2 yr
Site of first recurrence
Brain metastasis at diagnosis
Adjunvant endocrine therapy
Treatments received by patients within the two cohorts
Chemotherapies and endocrine therapies for the treatment of recurrent breast cancer for the two cohorts
(n = 170)
(n = 237)
No. of Patients
No. of Patients
Hormone therapy, %
HER2 targeting therapy, %
Survival of recurrent breast cancer patients within the two cohorts
Cox univariate and multivariate analysis of the survival in recurrent breast cancer
No. of axillary nodes involved
≤ 3 nodes
0.39 - 0.62
0.60 - 1.10
Adjuvant endocrine therapy
Relapse free interval
≤ 2 yr
Site of first recurrence
Brain metastatasis at diagnosis
AIs and/or trastuzumab for recurrent disease
0.34 - 0.55
Influence of HER-2 and HR status on survival between the two cohorts
Cox multivariate analysis of the survival in recurrent breast cancer by breast cancer subgroup
HR (95% CI)
HR (95% CI)
HR (95% CI)
HR (95% CI)
Age (>50 vs ≤50)
T stage (T3,4 vs T1,2)
No. of axillary nodes involved (3 < nodes vs ≤3 nodes)
HR status (positive vs negative)
HER-2 status (positive vs negative)
Adjuvant endocrine therapy (yes vs no)
Adjuvant chemotherapy (yes vs no)
Relapse free interval (>2 yr vs ≤ 2 yr)
Site of first recurrence (visceral vs non visceral)
Brain metastatasis at diagnosis (yes vs no)
AIs and/or trastuzumab for recurrent disease (yes vs no)
Time period (cohort B vs cohort A)
In this retrospective, single-institution study, we found that the survival of patients with recurrent breast cancer was significantly improved after the introduction of AIs and trastuzumab to the therapeutic regimen after 2001. Also, an improved prognosis was seen in patients with recurrent breast cancer that was related to HR and HER-2 expression. Patients with HR-positive and/or HER-2-positive tumors showed improved survival times after 2001; however, this was not the case for patients with HR-negative/HER-2-negative tumors.
There is a consensus of opinion that the survival of patients with recurrent, or metastatic, breast cancer has improved with the introduction of new agents [9, 10, 23]; however, it is not clear which particular therapy has been responsible for this improvement. Data from the French comprehensive cancer centers shows that increased survival time is associated with HR expression by the tumor . The hypothesis that the development of endocrine therapy has played an important role in increased survival rates is supported by the results of many randomized trials. Third-generation aromatase inhibitors (AI) recently became available for the treatment of breast cancer, and a number of randomized trials in postmenopausal women with advanced breast cancer have shown the superiority of AI over standard endocrine agents such as tamoxifen and megestrol acetate [24–26]. There seems to be partial non-cross resistance between different types of AIs [22, 27]. Exemestane (a steroidal AI) was shown to be effective after the failure of other non-steroidal AIs. In our study, a significant prolongation in survival time was seen in patients with HR-positive tumors within cohort B, which consisted of patients diagnosed and treated after the 2001, the year when AIs were first approved in Japan. This suggests that the survival rates of the HR-positive recurrent breast cancer patients improved due to treatment with AIs.
The introduction of HER-2 targeting therapies is also thought to have played an important role in the increased survival times. In HER-2-positive metastatic, or advanced, breast cancer, several clinical trials showed a significant clinical benefit of trastuzumab as a first-line chemotherapy agent [28, 29]. There is also some evidence from retrospective studies that metastatic breast cancer patients with HER-2-positve tumors benefit from the use of trastuzumab beyond disease progression [30, 31], and a recent randomized trial showed that continuation of trastuzumab-containing treatment was associated with a significant improvement in the overall response rate and time to progression after disease progression in patients with HER-2-positive metastatic breast cancer . In our study, significant improvements in survival times were seen in patients with HER-2-positive tumors in cohort B, suggesting that initial, or continued, treatment with trastuzumab was responsible.
As shown in previous reports [9, 32, 33], the presence of conventional adverse prognostic factors was shown to be associated with poor prognosis in this study (Table 3). The presence of visceral metastases, brain metastasis, HR status, and T stage and the number of axillary metastases significantly increased risk of death. However, even after taking these prognostic factors into account, the presence of AIs and/or trastuzumab treatment significantly decreased the hazard of death in multivariate analysis, and one could argue that the introduction of AIs and trastuzumab made the great contribution to the survival improvement. The time period was also shown to be a significant prognostic factor in multivariate analysis and recent time period conferred prolonged survival. There were also major differences between the two cohorts in terms of the other treatments received (i.e., the treatments other than AIs and trastuzumab). Other modern cytotoxic agents such as taxanes, capecitabine, and vinorelbine were used more frequently in cohort B. As shown in previous reports, the introduction of these new drugs for breast cancer treatment appears to have improved the survival rates of recurrent breast cancer patients [9, 10]. In addition, bisphosphonates have recently become available for the treatment of skeletal metastases, and have been shown to reduce the risk of bone-related events [34, 35]. Palliative care has also progressed. These advances in the treatment for recurrent breast cancer could be the reason why the time period was still a significant factor in this analysis.
As an exploratory analysis, we also investigated the association between survival improvement and breast cancer subtypes defined by HR and HER-2 status. Significant survival improvements were recognized in the HR-positive and/or HER-2-positive subtype after introduction of AIs and trastuzumab (Figure 2). With the introduction of these new agents, the breast cancer subtypes became closely related to the survival of patients with recurrent breast cancer. Regarding the HR-negative/HER-2-negative population, our study was underpowered in terms of demonstrating a significant survival benefit in this subtype, and indeed the prognosis was worse for this group than for the other tumor subtypes. This subtype is reported to be associated with aggressive behavior and poor prognosis [18, 36]. In a recent retrospective study of HR-negative/HER-2-negative breast cancer patients treated with modern chemotherapy, the median survival time from the diagnosis of metastatic lesions was only 13.3 months . This is far shorter than the median survival times reported in previous studies [9, 10, 37]. Exploratory analysis of data from the Cancer and Leukemia Group B 9342 study, which tested three doses of paclitaxel in women with advanced disease, showed that HR-negative/HER-2-negative tumors are associated with shorter overall survival rates compared with other subtypes . Our results showed that patients with HR-negative/HER-2-negative tumors had no significant prolongation of survival after trastuzumab treatment; the prognosis of these patients was only 1.4 years, even after the introduction of AI, trastuzumab and other new agents such as taxanes, vinorelbine and capecitabine. However, it is important to mention that this subgroup analysis was not part of the original study design, and that there was not enough statistical power to lead to a definitive conclusion. Therefore, this finding must be interpreted with caution.
We acknowledge that our study has several important limitations. First, this was a retrospective study, and thus subject to all the biases inherent to a retrospective design. Some degree of bias was present in the unadjusted analysis due to the weighting of more favorable prognostic factors, reduced number of lymph node metastases, reduced incidence of visceral metastasis, increased incidence of HR-positive, and longer RFI, in the groups that developed recurrent disease in more recent years. Earlier reports confirmed that patients with metastatic disease who had shorter disease-free survival times, HR-negative tumors, and visceral metastases, had significantly worse survival rates . Although the time period was shown to be a significant prognostic factor in the multivariate analysis, one could argue that these biases led to the survival improvement over time. Second, only 72% of the patients who were treated for recurrent disease were analyzed in this single-institution retrospective study. We cannot exclude the possibility that the analyzed population could have been biased as compared with the original cohort. Third, this study employed only a relatively small sample from a single institute and thus lacked the statistical power to lead to a definitive conclusion. Forth, information of survival curve beyond 4 years shown in Figure 2 may be little value due to the low numbers at risk. Further examination with larger number of cases is warranted to certify our findings.
In conclusion, our study suggests that the survival rates of women with recurrent breast cancer significantly improved after the introduction of AI and trastuzumab, and that the survival improvement was most pronounced in the HR-positive and/or HER-2-positive subgroup. The prognosis for HR-negative/HER-2-negative recurrent breast cancer patients was still poor and development of new therapies for this population is warranted.
contributions of the authors
HK planned the data analysis, carried out all statistical analyses, interpreted the results, and drafted the manuscript. YN contributed to the interpretation of the data and revised the manuscript for important intellectual content. SS, CK, KT and SN participated in the design of the study and revised the manuscript. Pathologists KT and KN evaluated the results of the immunohistochemical analysis. SO conceived of the study, participated in its design and coordination, and revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
third generation aromatase inhibitors
relapse free interval
enzyme immunoassay method
This study was supported in part by a Grant-in-Aid for Research on Cancer Treatment from the Ministry of Health, Labor, and Welfare of Japan (No. 21-7).
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